The proposed training in the K23 application outlines an integrated plan of mentored research and career development activities as well as a specific strategy for this pediatric gastroenterologist to pursue an independent research career as a physician scientist. This award will allow her to refine existing and to gain additional skills wit the guidance of her mentors, Drs. Wu and Lewis. To facilitate career development, she will complete the research plan for hands on training. Additionally, she will pursue formal coursework and one- on-one training from her mentors and members of her advisory committee with a focus on computational biology. Inflammatory bowel disease (IBD) is a complex genetic disorder in which multiple genetic polymorphisms lead to dysregulation of the intestinal mucosal immune system in response to environmental factors, perhaps the most important of which is the gut microbiota. Fundamentally, the loss of immune tolerance leads to an unrestrained immune response to commensal microbes normally resident in the gut. Current modalities of treatments for IBD do not focus on restoring immune tolerance, but rather depend on immunosuppression. Although highly effective in inducing and maintaining remission for many patients, there is a substantial risk of side effects associated with the use of steroids, immunomodulators, and biologics. In addition, a significant proportion of patients experience a loss of response to immune suppression over time. And despite advances in the therapeutic approach to patients with IBD in the past decade, there are still patients who demonstrate primary nonresponse to even the most powerful therapies. Based on the notion that environmental factors play a greater role in the risk for the development of IBD relative to genetics, an alternative or adjunctive strategy to treat IBD might include altering the environment by deep modification of the gut microbiota. This proposal will test the overarching hypothesis that a therapeutic approach that more deeply alters the composition and bacterial/fungal load of the gut microbiota will lead to efficacy in patients with Crohn's disease (CD). The studies proposed here will evaluate the efficacy of a novel treatment regimen, employing microbiota-targeted, nonimmunosuppressive medications, in the management of refractory ileocolonic Crohn's disease (Aim 1). These studies will also advance the understanding of the role of the gut microbiota in this vulnerable population (Aims 2 and 3).